Premium
Deactivation of Fibroblasts and Reduction of Fibrosis by Target‐Specific Copper Supplementation in Rhesus Monkey Model of Myocardial Ischemic Infarction
Author(s) -
Xiao Ying,
Nie Xin,
Liu Yinjie,
Han Pengfei,
Kang Y. James
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.301.2
Subject(s) - vimentin , sirius red , fibrosis , myocardial infarction , myofibroblast , myocardial fibrosis , medicine , immunostaining , western blot , cardiac function curve , pathology , infarction , cardiology , immunohistochemistry , chemistry , heart failure , biochemistry , gene
Activation of fibroblasts to myofibroblasts post ischemic injury hastens cardiac fibrosis and further impairs cardiac function. Copper supplementation reverses cardiac fibrosis and improves cardiac function. This study was undertaken to understand the link between changes in fibroblasts and the reduction of cardiac fibrosis. Male Rhesus monkeys of 4–5 years old were subjected to coronary artery ligation to induce myocardial infarction. At the end of fourth week after the surgery, a newly‐invented ultrasound‐directed Cu‐albumin microbubble organ‐specific Cu delivery technique was used to treat myocardial infarct monkeys twice a week for four weeks. Then the hearts were harvested, the infarct tissue was separated from unaffected tissue, and all of the tissue samples were collected for qRT‐PCR, Western blot, Sirius red staining, or immunostaining analyses. Cu‐albumin microbubble and ultrasound treatment significantly increased Cu concentrations in the infarcted area, reduced the infarct size, and loosened the collagen cross linking network. Total fibroblasts labeled with vimentin were increased in the infarct area, and this increase was not changed after Cu treatment. Activated fibroblasts, myofibroblasts, labeled with both vimentin and α‐SMA were significantly increased in the infarcted area, and Cu treatment significantly diminished the increase along with decreased mRNA levels of type I and III collagens. In addition, metalloproteinase‐1 (MMP‐1), a major MMP involved in collagen de‐crosslinking and degradation, was significantly increased, and the MMP‐1 secreting fibroblasts (vimentin + MMP‐1 + cells) were also significantly increased after Cu treatment. These results thus suggested that Cu induced deactivation of fibroblasts was associated with the reduction of collagen synthesis and the increase in collagen degradation in the infarct myocardium, leading to the breakage of collagen crosslinking along with the reduction in cardiac infarct size. Support or Funding Information This study was supported by National Science Foundation of China (81230004 and 81300109).Cu‐treatment reduced the infarct size, and loosened the collagen cross linking networkTotal fibroblasts were increased in the infarct area, and this increase was not changed after Cu treatment.Myofibroblasts were significantly increased in the infarcted area, and Cu treatment significantly diminished the increase along with decreased mRNA levels of type I and III collagens.MMP‐1 secreting fibroblasts (vimentin + MMP‐1 + cells) were also significantly increased after Cu treatment.